K. S. McCully et al. (American Journal of Pathology, 56, pp. 111-128, 1969) first reported the association of blood plasma homocysteine levels with risk from cardiovascular disease. McCully et al. identified a correlation between elevated plasma homocysteine concentrations and arteriosclerotic disease. More recent studies have determined that even moderately elevated plasma homocysteine levels are indicative of substantially increased risk to coronary heart disease, cerebrovascular disease, and peripheral vascular disorders. See, for example, J. Selhub et al., New England Journal of Medicine, 32, pp. 286-291, 1995, and S. Kang et al., Annual Review of Nutrition, 12, pp. 279-298, 1992.
With respect to assessing risk to cardiovascular disease, there is substantial evidence that elevated homocysteine levels may be a better predictor of risk than elevated cholesterol levels. For example, in one study, plasma homocysteine concentrations only 12% above the upper limit of normal were associated with a 3.4-fold increase in risk for myocardial infarction (M. Stampfer et al., Journal of the American Medical Association, 268, pp. 877-881, 1992). In another case study where blood was drawn before cardiovascular disease was diagnosed, a group of 271 men (who later suffered myocardial infarctions) presented significantly higher levels of homocysteine than control patients who did not later suffer infarctions (see P. Ueland et al., Cardiovascular Disease, Hemostasis and Endothelial Function, 1992, at pages 183-236, Marcel Dekker, New York).
O. Nygard et al., New England Journal of Medicine, 337(4), pp. 230-236 (1997) report that total plasma homocysteine is a strong predictor of mortality in patients with confirmed coronary artery disease.
A detailed understanding of the molecular mechanisms whereby homocysteine participates in cardiovascular disease processes has not yet been achieved. It has been suggested that homocysteine participates in reactions resulting, for example, in overproduction of oxygen free radicals, elastase activation, and calcium deposition (i.e. plaque formation). For a review of current theories, see K. McCully, Nature Medicine, 2(4), pp. 386-389 (1996) and K. S. McCully, Annals of Clinical and Laboratory Science, 23(6), pp. 477-493 (1993). Elevated levels of circulating homocysteine may also affect the coagulation process directly (see O. Nygard et al., above, and references cited therein).
Accordingly, there is a need to develop accurate methods to determine homocysteine levels in patients, and to make such assays a recognized part of standard medical practice. As described below, there is also a critical need to make available widespread screening of infants for diseases involving abnormal homocysteine metabolism, such as homocystinuria.